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Anticonvulsant-induced downbeat nystagmus in epilepsy
Epilepsy & Behavior Case Reports 4 (2015) 74–75
Contents lists available at ScienceDirect
Epilepsy & Behavior Case Reports journal homepage: www.elsevier.com/locate/ebcr
Case Report
Anticonvulsant-induced downbeat nystagmus in epilepsy Dongyan Wu a,b, Roland D. Thijs a,c,⁎ a b c
Stichting Epilepsie Instellingen Nederland (SEIN) — Heemstede, The Netherlands Institute of Neurology, Huashan Hospital, Fudan University, #12 Wulumuqi Zhong Rd., Shanghai 200040, China Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 7 July 2015 Accepted 8 July 2015 Available online 27 August 2015 Keywords: Downbeat nystagmus Anticonvulsants Toxicity Adverse effects Epilepsy
a b s t r a c t We report data from two patients who developed reversible downbeat nystagmus (DBN) while using AEDs within the therapeutic range. All previous reported cases of epilepsy with drug-induced DBN related to toxic levels of AEDs were summarized, and DBN was found mostly occurring in those using a sodium channel blocking AED. We propose that in our cases, the DBN with therapeutic AED levels may be explained by additive effects of sodium channel blockers. Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2. Case reports
partial seizures despite taking multiple AEDs. The complaints started following a change of medication: introduction of lacosamide 100 mg bid and tapering of topiramate. At the time of referral, she used valproic acid, levetiracetam, lamotrigine, and topiramate (Table 1). The oscillopsia was continuous without clear fluctuations following drug intake. Downbeat nystagmus and ataxia were noted at examination. There was no evidence of AED intoxication (Table 1). Lacosamide was discontinued, and the DBN and ataxia disappeared.
2.1. Case 1
3. Discussion
A 30-year-old man with refractory epilepsy following perinatal occipital lobe infarction was referred to our center with episodes of oscillopsia 1 h after taking his AEDs (lamotrigine 150 mg bid, valproic acid 600 mg bid, gabapentin 400 mg tid, and carbamazepine 400 mg bid). He noted that oscillopsia while reading could be prevented by keeping his book upward. He had DBN on examination. All AED levels were within the therapeutic range (Table 1). Downbeat nystagmus disappeared immediately after reduction of lamotrigine; subsequently, gabapentin was withdrawn without seizure increase.
In these cases, the drug levels were within the therapeutic range, but the temporal relationship between oscillopsia and drug ingestion (Case 1), the response to change to the drug treatment (Case 1 and Case 2), and also the impressive amount of AEDs suggested a drug-related cause. An ultimate proof would require a drug challenge, but this was not feasible in these cases. Downbeat nystagmus is thought to result from impairment of the vestibulocerebellum, flocculus, or paraflocculus, that serves as the output pathway for information on movement, coordination, and balance from the cerebellar cortex [1–3]. In our two cases, the relevant drugs lamotrigine and lacosamide are both sodium channel blockers. In addition, both subjects were on combination therapy with other AEDs with sodium channel blocking properties (carbamazepine and valproic acid in Case 1, lamotrigine and valproic acid in Case 2). We reviewed the PubMed database (search terms: DBN and epilepsy) and identified nine previously reported cases with epilepsy and drug-induced DBN (Table 1). Most cases were related to toxic AED levels (lamotrigine, phenytoin, and felbamate). In one case, lamotrigine toxicity was likely, but not established; in another case, DBN was associated with therapeutic
1. Introduction Iatrogenic down beat nystagmus (DBN) in people with epilepsy is rare and has been reported in the context of intoxication with antiepileptic drugs (AEDs) [1]. We describe two patients who developed reversible DBN while using AEDs within the therapeutic range.
2.2. Case 2 A 38-year-old woman with refractory epilepsy due to tuberous sclerosis complex and a hypothalamic giant cell astrocytoma presented with oscillopsia. She had weekly clusters of predominantly complex ⁎ Corresponding author at: Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. Tel.: +31 23 558 8940; fax: +31 23 558 8159. E-mail address: [email protected] (R.D. Thijs).
http://dx.doi.org/10.1016/j.ebcr.2015.07.003 2213-3232/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Wu, R.D. Thijs / Epilepsy & Behavior Case Reports 4 (2015) 74–75
75
Table 1 Summary of previous reported and presented cases with epilepsy and anticonvulsant-induced downbeat nystagmus (DBN).
Age Sex Etiology
23
F
Specific cause
Unknown
Medication: total daily dosage (mg)
AED serum levels with, without DBN (μg/ml)
Absence of DBN following AED reduction (R) or withdrawal (W)
Lorazepam 2 Lamotrigine 400 Lamotrigine 500
Gabapentin 1200
Lamotrigine 19.9#
Lamotrigine (R)
Lamotrigine 600
Lamotrigine 27.0 , 18.8 Carbamazepine 9.4
Perphenazine 12 Thioridazine 200
Phenytoin 38#, 18 Phenytoin 27#, 14 Phenobarbital 24
Primidone 750 Acetazolamide 1000 Methosuximide 600
34
F
Structural Meningitis
31
F
Unknown
51 54
M F
Structural Gunshot Unknown
19
F
Unknown
23
F
Structural Adhesions found in posterior fossa (Meningitis?)
Carbamazepine 1200 Topiramate 200 Phenytoin 400 Phenytoin 400 Phenobarbital 120 Primidone 250 Phenytoin 150 Carbamazepine 800 Primidone 750 Phenytoin 300 Carbamazepine 800
18
F
Unknown
Carbamazepine 1800
44
M
Structural Concussion
30
M
38
F
Structural Perinatal occipital lobe infarction Structural Tuberous sclerosis complex; hypothalamic giant cell astrocytoma
Felbamate (dosage not reported) Valproic acid 1200 Carbamazepine 1200 Valproic acid 2000 Levetiracetam 2000
Valproic acid 1250
Haloperidol 3 Benztropine 2 Lamotrigine 300 Gabapentin 3600 Lamotrigine 200 Lacosamide 200
#
Reference [4]
Valproic acid (R) [4] Lamotrigine not assessed
Lamotrigine (R)
[5]
Primidone 6.3
Phenytoin (W) Phenytoin (W)
[6] [6]
Phenytoin 14, 14
Primidone 22#, 15
Phenytoin (R)
[7]
Phenytoin 20#, 9.8 Primidone 6
Carbamazepine 3.5 Methsuximide 1.7
Phenytoin (W)
[7]
Carbamazepine (R) Felbamate (W)
[8]
Lamotrigine (R) Gabapentin (W) Lacosamide (W)
This paper
Carbamazepine 9.6, 6.9 Felbamate 110# Valproic acid 65, 44 Carbamazepine 8.4, 6.8 Valproic acid 74, 53 Levetiracetam 19.1, 23.2
Lamotrigine 9.08, 6.8 Gabapentin 11.5, 3.8 Lamotrigine 7.6, 7.1 Lacosamide 5.0
[9]
This paper
DBN = downbeat nystagmus, AED = antiepileptic drug, F = female, M = male. # Toxic level.
levels of carbamazepine. As in our cases, all subjects suffered from refractory epilepsy, and most (7 out of 9) were using multiple AEDs. All AEDs that have been associated with DBN (carbamazepine, phenytoin, lacosamide, and lamotrigine) have sodium channel blocking properties except for felbamate. Voltage-gated sodium channel (Nav) 1.1 and Nav1.6 channels are the primary voltage-activated sodium channel isoforms expressed in cerebellar Purkinje neurons and might explain the association between DBN and sodium channel blocking AEDs [10]. We suggest that the occurrence of DBN within the therapeutic range may be explained by additive effects of sodium channel blockers as in our two cases or by an increased propensity for DBN due to epilepsy etiology (e.g., encephalopathy with cerebellar dysfunction). 4. Conclusion Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs, particularly those with sodium channel blocking properties even in the absence of toxic levels. Prompt recognition of this adverse effect is important to avoid an incorrect diagnosis. Ethical standard We confirm that we have read the Journal's position on issues involved in ethical publication and confirm that this report is consistent with the guidelines.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References [1] Leigh RJ, Khanna S. What can acquired nystagmus tell us about congenital forms of nystagmus? Semin Ophthalmol 2006;21:83–6. [2] Zee DS, Friendlich AR, Robinson DA. The mechanism of downbeat nystagmus. Arch Neurol 1974;30:227–37. [3] Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 1981;46:878–99. [4] Alkawi A, Kattah JC, Wyman K. Downbeat nystagmus as a result of lamotrigine toxicity. Epilepsy Res 2005;63:85–8. [5] Oh SY, Kim JS, Lee YH, Lee AY, Kim J, Kim JM. Downbeat, positional, and perverted head-shaking nystagmus associated with lamotrigine toxicity. J Clin Neurol 2006; 2:283–5. [6] Berger JR, Kovacs AG. Downbeat nystagmus with phenytoin. J Clin Neuroophthalmol 1982;2:209–11. [7] Alpert JN. Downbeat nystagmus due to anticonvulsant toxicity. Ann Neurol 1978;4: 471–3. [8] Chrousos GA, Cowdry R, Schuelein M, Abdul-Rahim AS, Matsuo V, Currie JN. Two cases of downbeat nystagmus and oscillopsia associated with carbamazepine. Am J Ophthalmol 1987;103:221–4. [9] Hwang TL, Still CN, Jones JE. Reversible downbeat nystagmus and ataxia in felbamate intoxication. Neurology 1995;45:846. [10] Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J Neurosci 2007;27:11065–74.
Contents lists available at ScienceDirect
Epilepsy & Behavior Case Reports journal homepage: www.elsevier.com/locate/ebcr
Case Report
Anticonvulsant-induced downbeat nystagmus in epilepsy Dongyan Wu a,b, Roland D. Thijs a,c,⁎ a b c
Stichting Epilepsie Instellingen Nederland (SEIN) — Heemstede, The Netherlands Institute of Neurology, Huashan Hospital, Fudan University, #12 Wulumuqi Zhong Rd., Shanghai 200040, China Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 7 July 2015 Accepted 8 July 2015 Available online 27 August 2015 Keywords: Downbeat nystagmus Anticonvulsants Toxicity Adverse effects Epilepsy
a b s t r a c t We report data from two patients who developed reversible downbeat nystagmus (DBN) while using AEDs within the therapeutic range. All previous reported cases of epilepsy with drug-induced DBN related to toxic levels of AEDs were summarized, and DBN was found mostly occurring in those using a sodium channel blocking AED. We propose that in our cases, the DBN with therapeutic AED levels may be explained by additive effects of sodium channel blockers. Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2. Case reports
partial seizures despite taking multiple AEDs. The complaints started following a change of medication: introduction of lacosamide 100 mg bid and tapering of topiramate. At the time of referral, she used valproic acid, levetiracetam, lamotrigine, and topiramate (Table 1). The oscillopsia was continuous without clear fluctuations following drug intake. Downbeat nystagmus and ataxia were noted at examination. There was no evidence of AED intoxication (Table 1). Lacosamide was discontinued, and the DBN and ataxia disappeared.
2.1. Case 1
3. Discussion
A 30-year-old man with refractory epilepsy following perinatal occipital lobe infarction was referred to our center with episodes of oscillopsia 1 h after taking his AEDs (lamotrigine 150 mg bid, valproic acid 600 mg bid, gabapentin 400 mg tid, and carbamazepine 400 mg bid). He noted that oscillopsia while reading could be prevented by keeping his book upward. He had DBN on examination. All AED levels were within the therapeutic range (Table 1). Downbeat nystagmus disappeared immediately after reduction of lamotrigine; subsequently, gabapentin was withdrawn without seizure increase.
In these cases, the drug levels were within the therapeutic range, but the temporal relationship between oscillopsia and drug ingestion (Case 1), the response to change to the drug treatment (Case 1 and Case 2), and also the impressive amount of AEDs suggested a drug-related cause. An ultimate proof would require a drug challenge, but this was not feasible in these cases. Downbeat nystagmus is thought to result from impairment of the vestibulocerebellum, flocculus, or paraflocculus, that serves as the output pathway for information on movement, coordination, and balance from the cerebellar cortex [1–3]. In our two cases, the relevant drugs lamotrigine and lacosamide are both sodium channel blockers. In addition, both subjects were on combination therapy with other AEDs with sodium channel blocking properties (carbamazepine and valproic acid in Case 1, lamotrigine and valproic acid in Case 2). We reviewed the PubMed database (search terms: DBN and epilepsy) and identified nine previously reported cases with epilepsy and drug-induced DBN (Table 1). Most cases were related to toxic AED levels (lamotrigine, phenytoin, and felbamate). In one case, lamotrigine toxicity was likely, but not established; in another case, DBN was associated with therapeutic
1. Introduction Iatrogenic down beat nystagmus (DBN) in people with epilepsy is rare and has been reported in the context of intoxication with antiepileptic drugs (AEDs) [1]. We describe two patients who developed reversible DBN while using AEDs within the therapeutic range.
2.2. Case 2 A 38-year-old woman with refractory epilepsy due to tuberous sclerosis complex and a hypothalamic giant cell astrocytoma presented with oscillopsia. She had weekly clusters of predominantly complex ⁎ Corresponding author at: Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. Tel.: +31 23 558 8940; fax: +31 23 558 8159. E-mail address: [email protected] (R.D. Thijs).
http://dx.doi.org/10.1016/j.ebcr.2015.07.003 2213-3232/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Wu, R.D. Thijs / Epilepsy & Behavior Case Reports 4 (2015) 74–75
75
Table 1 Summary of previous reported and presented cases with epilepsy and anticonvulsant-induced downbeat nystagmus (DBN).
Age Sex Etiology
23
F
Specific cause
Unknown
Medication: total daily dosage (mg)
AED serum levels with, without DBN (μg/ml)
Absence of DBN following AED reduction (R) or withdrawal (W)
Lorazepam 2 Lamotrigine 400 Lamotrigine 500
Gabapentin 1200
Lamotrigine 19.9#
Lamotrigine (R)
Lamotrigine 600
Lamotrigine 27.0 , 18.8 Carbamazepine 9.4
Perphenazine 12 Thioridazine 200
Phenytoin 38#, 18 Phenytoin 27#, 14 Phenobarbital 24
Primidone 750 Acetazolamide 1000 Methosuximide 600
34
F
Structural Meningitis
31
F
Unknown
51 54
M F
Structural Gunshot Unknown
19
F
Unknown
23
F
Structural Adhesions found in posterior fossa (Meningitis?)
Carbamazepine 1200 Topiramate 200 Phenytoin 400 Phenytoin 400 Phenobarbital 120 Primidone 250 Phenytoin 150 Carbamazepine 800 Primidone 750 Phenytoin 300 Carbamazepine 800
18
F
Unknown
Carbamazepine 1800
44
M
Structural Concussion
30
M
38
F
Structural Perinatal occipital lobe infarction Structural Tuberous sclerosis complex; hypothalamic giant cell astrocytoma
Felbamate (dosage not reported) Valproic acid 1200 Carbamazepine 1200 Valproic acid 2000 Levetiracetam 2000
Valproic acid 1250
Haloperidol 3 Benztropine 2 Lamotrigine 300 Gabapentin 3600 Lamotrigine 200 Lacosamide 200
#
Reference [4]
Valproic acid (R) [4] Lamotrigine not assessed
Lamotrigine (R)
[5]
Primidone 6.3
Phenytoin (W) Phenytoin (W)
[6] [6]
Phenytoin 14, 14
Primidone 22#, 15
Phenytoin (R)
[7]
Phenytoin 20#, 9.8 Primidone 6
Carbamazepine 3.5 Methsuximide 1.7
Phenytoin (W)
[7]
Carbamazepine (R) Felbamate (W)
[8]
Lamotrigine (R) Gabapentin (W) Lacosamide (W)
This paper
Carbamazepine 9.6, 6.9 Felbamate 110# Valproic acid 65, 44 Carbamazepine 8.4, 6.8 Valproic acid 74, 53 Levetiracetam 19.1, 23.2
Lamotrigine 9.08, 6.8 Gabapentin 11.5, 3.8 Lamotrigine 7.6, 7.1 Lacosamide 5.0
[9]
This paper
DBN = downbeat nystagmus, AED = antiepileptic drug, F = female, M = male. # Toxic level.
levels of carbamazepine. As in our cases, all subjects suffered from refractory epilepsy, and most (7 out of 9) were using multiple AEDs. All AEDs that have been associated with DBN (carbamazepine, phenytoin, lacosamide, and lamotrigine) have sodium channel blocking properties except for felbamate. Voltage-gated sodium channel (Nav) 1.1 and Nav1.6 channels are the primary voltage-activated sodium channel isoforms expressed in cerebellar Purkinje neurons and might explain the association between DBN and sodium channel blocking AEDs [10]. We suggest that the occurrence of DBN within the therapeutic range may be explained by additive effects of sodium channel blockers as in our two cases or by an increased propensity for DBN due to epilepsy etiology (e.g., encephalopathy with cerebellar dysfunction). 4. Conclusion Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs, particularly those with sodium channel blocking properties even in the absence of toxic levels. Prompt recognition of this adverse effect is important to avoid an incorrect diagnosis. Ethical standard We confirm that we have read the Journal's position on issues involved in ethical publication and confirm that this report is consistent with the guidelines.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References [1] Leigh RJ, Khanna S. What can acquired nystagmus tell us about congenital forms of nystagmus? Semin Ophthalmol 2006;21:83–6. [2] Zee DS, Friendlich AR, Robinson DA. The mechanism of downbeat nystagmus. Arch Neurol 1974;30:227–37. [3] Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 1981;46:878–99. [4] Alkawi A, Kattah JC, Wyman K. Downbeat nystagmus as a result of lamotrigine toxicity. Epilepsy Res 2005;63:85–8. [5] Oh SY, Kim JS, Lee YH, Lee AY, Kim J, Kim JM. Downbeat, positional, and perverted head-shaking nystagmus associated with lamotrigine toxicity. J Clin Neurol 2006; 2:283–5. [6] Berger JR, Kovacs AG. Downbeat nystagmus with phenytoin. J Clin Neuroophthalmol 1982;2:209–11. [7] Alpert JN. Downbeat nystagmus due to anticonvulsant toxicity. Ann Neurol 1978;4: 471–3. [8] Chrousos GA, Cowdry R, Schuelein M, Abdul-Rahim AS, Matsuo V, Currie JN. Two cases of downbeat nystagmus and oscillopsia associated with carbamazepine. Am J Ophthalmol 1987;103:221–4. [9] Hwang TL, Still CN, Jones JE. Reversible downbeat nystagmus and ataxia in felbamate intoxication. Neurology 1995;45:846. [10] Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J Neurosci 2007;27:11065–74.